Streptococcus equi subspecies zooepidemicus was previously reported as an important swine pathogen only in Asia. Here we report the isolation and whole genome characterization of S. equi subsp. zooepidemicus associated with a sudden death outbreak in pigs in Canada. Historically described as a commensal of the swine upper respiratory tract,  Streptococcus equi subspecies zooepidemicus is considered a commensal and opportunistic pathogen of several warm-blooded hosts, including humans, horses, canines, and swine. It is a gram-positive, β-hemolytic coccus belonging to the Lancefield group C and can cause severe disease characterized by pneumonia, septicemia, and meningitis  in a large vertically integrated swine system in Manitoba, Canada. This outbreak increased the cumulative death in the 3 affected sow herds by >1,000 animals over a 12-week period. The abortion rate during this time was »11× normal. The sows were often described as apparently healthy during morning checks. However, over the course of hours, infected sows would become unwilling to stand, develop fever and lethargy, then die with no other apparent clinical signs. Other sows would abort and then go on to develop similar symptoms. Stress factors, such as mixing groups of sows and the presence of other sick animals, appeared to exacerbate outbreaks within pens. Mycoplasma hyopneumoniae, simian immunodeficiency virus A, and porcine circovirus types 2 and 3; results were negative for each. Animals were electronically fed a commercial grade, nutritionally balanced diet and had ad libitum access to water. Gross postmortem examination of multiple animals, either euthanized or recently deceased, revealed rhinitis ; pulmonary edema; gall bladder edema; and hemorrhagic lymphadenopathy (tan-colored to hemorrhagic), consisting of submandibular, cervical neck, and bronchial lymph nodes. These signs, taken together, suggest sepsis. We used real-time PCR to test all of the dead sows for porcine reproductive and respiratory syndrome virus, S. equi subsp. zooepidemicus in liver, kidney, heart, brain, lung, spleen, and submandibular lymph nodes. Isolate identification was confirmed by 2 different veterinary diagnostic laboratories. We found isolates SAMN13058951, SAMN13058952, SAMN13058953, SAMN13058954, SAMN13058955, SAMN13058956, and SAMN13058957 resistant to lincomycin, neomycin, and tetracycline and susceptible to ampicillin, ceftiofur, penicillin, and tilmicosin in a Kirby-Bauer disk diffusion assay. In parallel, we observed gram-positive cocci in imprints from heart and submandibular lymph nodes. After aerobic bacterial culture followed by matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry for identification of isolates revealed varying levels of https://www.qiagen.com), quantified by Nanodrop (3300) and PicoGreen , then processed it for sequencing using a Illumina Nextera XT library prep kit . We performed sequencing using MiSeq Nano V2, 2×250 paired-end (Illumina). Samples yielded an average of 149,017 high quality reads, suggesting 50× coverage. We conducted genome assembly, annotation, and downstream analyses using the PATRIC package , rpoB (rifampin-resistant), S10p (tetracycline-resistant), kasA (triclosan-resistant), PgsA, LiaR, LiaS (daptomycin-resistant), folA, Dft (trimethoprim-resistant), folP (sulfadiazine-resistant), and FabK (triclosan-resistant). Virulence factors found, including the previously described szm, szp, lmb, fbpZ, skc, and has operons and mga regulon (All isolates were similar to previously published  genomes , demonstS. equi subsp. zooepidemicus sequence type 194 as a cause of death in pigs in Canada and possibly other regions of North America. This specific sequence type seems to be particularly virulent to pigs, for reasons that remain unexplained. Given the clinical presentation described here, this pathogen requires special attention and should no longer be overlooked when conducting diagnostic investigations, despite its historically accepted status as a commensal organism. Taken together, these findings suggest the emergence of


Die mit der COVID-19-Pandemie einhergehenden Kontaktbeschränkungen haben viele Unternehmen dazu veranlasst, ihren Beschäftigten aus Gründen des Infektionsschutzes das Arbeiten aus dem Homeoffice zu ermöglichen.In dieser Literaturübersicht wird der Frage nachgegangen, inwiefern die Ausübung der beruflichen Tätigkeit im Homeoffice gesundheitsfördernd gestaltet werden kann.Arbeitsplätzen im Homeoffice liegen dieselben Richtlinien wie für Büro- und Bildschirmarbeitsplätze zugrunde. Um negative psychische und physische Beanspruchungsfolgen zu vermeiden, wird die ergonomische Arbeitsplatzgestaltung empfohlen. Außerdem kommt der Arbeitszeitgestaltung  eine hohe Bedeutung für eine gesundheitsfördernde Arbeitsweise im Homeoffice zu.Wichtige Bausteine für gesundheitsfördernde Arbeitsgestaltung sind die zeitliche, räumliche und insbesondere mentale Trennung von Arbeits- und Privatleben. Bei der gesundheitsfördernden Arbeitsplatzgestaltung im Homeoffice sind Beschäftigte und ihre individuellen Bedürfnisse zu berücksichtigen. Die Verantwortung der Realisierung gesundheitsfördernder Arbeitsgestaltung liegt durch die ad-hoc-Umstellung in der Pandemie jedoch zumeist allein bei den Beschäftigten. Die COVID-19-Pandemie  führte dazu, im Sinne des Infektionsschutzes, viele Beschäftigte kurzfristig ins Homeoffice zu entsenden . Im KontBasierend auf dem Beschluss der Bundesregierung vom 15. April 2020 „Beschränkungen des öffentlichen Lebens zur Eindämmung der COVID-19-Epidemie“  haben viDie Einrichtung eines ergonomischen Arbeitsplatzes im Homeoffice stellt indes eine maßgebende Herausforderung unter den aktuellen Umständen der COVID-19-Pandemie dar.Neue Arbeitssituation im Homeoffice unterliegt besonderem AugenmerkWissenschaftliche Ergebnisse deuten darauf hin, dass die Überlagerung von Berufs- und Privatleben von verschiedenen psychischen Belastungsfaktoren und Ressourcen gekennzeichnet ist . Häufig Vor dem Hintergrund dieser Herausforderungen behandelt dieser Übersichtsartikel die gesundheitsfördernde Arbeitsgestaltung im Homeoffice in Zeiten der COVID-19-Pandemie unter besonderer Berücksichtigung der Themenfelder (ergonomische) Arbeitsplatzgestaltung, Arbeitszeitgestaltung und Regeneration. Zugrunde liegen in erster Linie wissenschaftliche Studien, die die gesundheitsfördernde Arbeitsgestaltung im Homeoffice fokussieren, anhand einer explorativen Literaturrecherche in wissenschaftlichen Datenbanken, u. a. PubMed und PsychINFO, recherchiert. Außerdem wird sich auf die geltenden gesetzlichen Normen und Verordnungen gestützt. Unter Arbeitsgestaltung wird in diesem Übersichtsartikel die Gestaltung von ergonomischen Arbeitsplätzen, Arbeits- und Erholungszeit gefasst. Nach der Beschreibung möglicher Herausforderungen werden praktische Umsetzungsempfehlungen für Arbeitgeber und Beschäftigte formuliert.Um psychische und physische Beanspruchungsfolgen zu vermeiden, muss die Arbeitsplatzgestaltung an die individuellen Bedürfnisse der Beschäftigten angepasst werden. Zur Reduzierung möglicher negativer Beanspruchungsfolgen können die Belastungen in ihrer Ausprägung u. a. durch technische (ergonomische), organisatorische und personenbezogene Maßnahmen für die Neu- bzw. Umgestaltung des Arbeitsplatzes im Homeoffice vermindert werden Darüber hinaus können regelmäßige Blicke in die Ferne die Augen bei längerer Bildschirmtätigkeit entspannen . Ein WecDie kurzfristige Umstellung der Arbeitsausführung in das Homeoffice während der COVID-19-Pandemie kann vielen Beschäftigten die Umsetzung ergonomischer Arbeitsplatzgestaltung erschweren , 30. InsDie im Homeoffice vorliegenden flexiblen und selbst zu gestaltenden Arbeitsbedingungen erfordern insbesondere Selbstmanagement- und Arbeitsgestaltungskompetenzen, wie z. B. Selbstführung und die Eigenverantwortung über die Strukturierung von Arbeitsaufgaben sowie Motivierungsstrategien . Eine daUnfreiwillige Arbeitsunterbrechungen können die Arbeitsproduktivität hingegen vermindern  und ebenDie Umstände der COVID-19-Pandemie bergen darüber hinaus weitere Herausforderungen in der Arbeitszeitgestaltung, denen sich insbesondere Eltern stellen mussten. Da Schulen und Kindertagesstätten zeitweise geschlossen waren, mussten im Homeoffice tätige Eltern ggf. zusätzlich ihre Kinder zu Hause betreuen und versorgen . Auch füDie Gestaltung von Ruhepausen und -zeiten (Pausen während und Regeneration nach der Arbeit) obliegt durch die besondere Arbeitssituation im Homeoffice einem besonderen Augenmerk. Die eigenverantwortliche Arbeitszeitgestaltung im Homeoffice birgt die Gefahr, dass über die regulären Zeiten hinaus gearbeitet wird. Dies kann für Beschäftigte im Homeoffice psychisch belastend sein . Im FallDie Realisierung einer gesundheitsfördernden Pausenorganisation obliegt laut § 3 ArbSchG als eine Grundpflicht dem Arbeitgeber. Gemäß § 15 des ArbSchG sind Beschäftigte entsprechend dazu verpflichtet, die gesetzlich verpflichtenden Pausenzeiten  einzuhalten . Ein potHomeoffice-Tätigkeit erfordert SelbstmanagementkompetenzenHierfür können unterstützende Methoden wie die Pomodoro-Technik  angewandNeben der physischen Distanzierung von der Arbeit, welche im Homeoffice maßgeblich erschwert sein kann, ist hierbei auch das mentale Abschalten von der Arbeit (sog. Detachment) von großer Relevanz. Arbeitsbezogene Belastungsfaktoren können mit geringem Detachment kombiniert zur Entstehung negativer Beanspruchungsfolgen beitragen. Studienergebnisse zeigen, dass Detachment psychische Arbeitsbelastungswirkungen und möglichen negativen Beanspruchungsfolgen (wie beispielsweise Ermüdung) abpuffern kann . Durch dGrundsätzlich sollten Arbeitgeber in der aktuellen Situation eine besonders beratende Funktion für Beschäftigte in Bezug auf ergonomische Arbeitsplatzgestaltung im Homeoffice einnehmen. Während der Tätigkeit im Homeoffice kann eine wechselnde Körperhaltung (sitzend/stehend) hilfreich sein . Die VerDie COVID-19-Pandemie stellt seit Anfang des Jahres 2020 eine aktuelle Public-Health-Herausforderung dar, welche auch die Arbeitswelt und ihre Beschäftigten vor anspruchsvolle Aufgaben stellt.Für die individuelle Gesundheit der Beschäftigten ist eine Kompetenzerweiterung, z. B. hinsichtlich der ergonomischen Arbeitsplatzgestaltung und Selbstorganisation, begleitet von guter Führungsarbeit, vorteilhaft, um in der neuen Arbeitssituation in der Pandemie gesundheitsfördernd arbeiten zu können.Eine entsprechende Organisations- und Führungskultur, welche die gesundheitlichen Bedarfe der Beschäftigten berücksichtigt sowie ihre Arbeitssicherheit und Gesundheit verstärkt in den Vordergrund stellt, ist unabdingbar.Betriebliche Abläufe, welche Aufklärung und Edukation miteinbeziehen, bergen großes Potenzial, die Gesundheit der Beschäftigten auch im Homeoffice langfristig und nachhaltig zu fördern und zu erhalten.


This paper analyzes, through computational simulations, which spectral filters increase the number of discernible colors (NODC) of subjects with normal color vision, as well as red–green anomalous trichromats and dichromats. The filters are selected from a set of filters in which we have modeled spectral transmittances. With the selected filters we have carried out simulations performed using the spectral reflectances captured either by a hyperspectral camera or by a spectrometer. We have also studied the effects of these filters on color coordinates. Finally, we have simulated the results of two widely used color blindness tests: Ishihara and Farnsworth–Munsell 100 Hue (FM100). In these analyses the selected filters are compared with the commercial filters from EnChroma and VINO companies. The results show that the increase in NODC with the selected filters is not relevant. The simulation results show that none of these chosen filters help color vision deficiency (CVD) subjects to pass the set of color blindness tests studied. These results obtained using standard colorimetry support the hypothesis that the use of color filters does not cause CVDs to have a perception similar to that of a normal observer. The study of color vision deficiencies (CVDs) has recently gained attention from social networks due to the appearance of companies that have developed what they call "aids" for subjects with CVD. Approximately 1 in 12 men and 1 in 200 women have some type of CVD ).Subjects whose color vision anomaly is between moderate and severe may suffer limitations in their daily lives, such as not distinguishing the degree of cooking of meat, the maturity of certain fruits and vegetables, the color of certain indicative lights (LEDs), different colors on maps, etc. For this reason, in most countries, these subjects are automatically excluded from certain jobs such as being an airplane pilot, firefighter, train driver, air traffic controller, etc. . Although genetic therapy experiments in mice and primates have been carried out , there aOn the other hand, passive aid is of interest, such as filters that can be worn in glasses or contact lenses. Despite the lack of scientific evidence on the improvement of color vision in CVD observers using any type of filters, companies manufacturing them  for different types of observers, as well as the effect that these filters have on color coordinates. At this point we would like to clarify that, as defined in Other authors have done work in this regard. Linhares et al.  investigMoreland et al. studied the effect of filters by simulations in . In thisMarín Franch and Foster  used infPastilha et al.  evaluateMasuda and Nascimento  studied In this study, we have investigated three types of filters: band-pass and notch whose transmittances have been simulated, and the two commercial models studied in previous research, from EnChroma  and VINOIn this study the spectral information was limited within the range from 400 nm to 700 nm (visible range), and sampled every 1 nm through linear interpolation. Three reflectance sets were used, each of them corresponding to three different types of objects or scenes. Simulations were carried out using D65 as illuminant following CIE  recommendations for the use of CIELAB color space . This isL*, a*, b* distribution in CIELAB color space.In order to select which filters, amongst the 90,922 simulated, maximized the NODC for each observer, a reduced but diverse hyperspectral reflectance set was used. This set was composed of the reflectances present in four popular color atlases: Munsell (1269 samples) , NCS , and each of them single and double. These types were considered since the existing passive aids usually feature this spectral shape. The filters were simulated using Gaussian functions (for the band-pass ones), and their complementary functions (for the notch ones). In the following sub-sections, we explain what each of these types of filters is like. Since increasing the width of a Gaussian function involves reducing the slope of its flanks, the rise and descent flank of a 10 nm bandwidth (FWHM) Gaussian function was used. These rise and descent flanks are separated more or less depending on the simulated band-pass or notch width of the filters. Thus, the simulated transmittances were more selective than normal width Gaussian functions but their spectral shapes are smoother than the step function, and hence more realistic. The pass-band for each filter (range between a rise flank and a descent flank) was considered with a maximum transmittance of 1. These filters block all wavelengths but those belonging to a specific spectral range . We simulated filters with central wavelengths varying from 400 nm to 700 nm, with a 10 nm step. Moreover, for each central wavelength, we simulated filters where the FWHM bandwidth varies from 10 to 100 nm in 10 steps. This was a total of 310 band-pass filters . In order to simulate them, all transmittances from the band-pass filters previously calculated were subtracted from the unity transmittance. Thus, another 310 notch filters were simulated R, which multiplied by the spectral radiance of the illuminant illum(λ)SPD, and by the spectral transmittance of the filter T(λ), yields the color signal color(λ)L, as shown in Equation (1).The initial data for simulations were: the spectral reflectance L*, a*, b*, abC* y abh. The reference white used for both unfiltered and filtered conditions was the same in order to be able to directly compare results between unfiltered and filtered cases.As mentioned in We need to clarify here that the most correct way to proceed would be to build a personalized set of transformations and functions to be used in colorimetry for each observer  using as a starting point the color-matching functions of each type of observer. However, this approach, besides being considerably complex, is still an open problem and there is no clear way to see it done in practical terms. Hence, standard colorimetry was used for CVD observers as it is usually done in the literature ,12,14,18L’) and deutan (M’) observers are calculated via the following Equations (2) and (3):L and M are the cone responses from a normal trichromat observer and parameter d represents the amount in which the responses from normal cones are combined to obtain the response from the anomalous cone. Thus, d is not directly related to the severity regarded as the spectral separation between L and M curves. However, this spectral separation is related to the increase of the chromatic discrimination threshold, as shown in [L and M maxima corresponds to a moderate/severe CVD condition. For this reason, we calculated the value of d corresponding to this spectral separation of 3 nm , using the cone response curves in [d.Once the tristimulus values were calculated for the D1 set and the normal observer, the tristimulus values for different CVD observers (type and severity) were simulated. There are several models in the literature for doing this ,16,17,19shown in , where turves in . Figure d = 1. In this study we have simulated five types of observers: observers with normal color vision, anomalous trichromat observers (protan07 and deutan09), and anomalous dichromat observers (protan10 and deutan10).To simulate dichromat subjects in an extreme case we use the severity parameter with a value of XYZ tristimulus values for the D1 samples and the five different observers simulated both with and without filters, we needed a metric evaluation in order to compare the performance of each filter for each observer. To do so we considered the number of discernible colors (NODC).After calculating abE > 1) [L*, a*, b* color space in cubes of 1 unit sides, and count in how many of them there is at least one sample [If we assume that two colors are discernible when their CIELAB space color difference is above 1 unit (ΔEab > 1) , we can e sample . This mee sample , this isThis section is divided into two sub-sections. In the first, the NODC for all the simulated filters is computed, and the filter that maximizes NODC for database D1 is determined. In the second sub-section, the effect of the filters that maximize NODC on color coordinates, sRGB rendering of the scenes, and the Ishihara and FM-100 simulations are explained.The NODC has been computed for the five types of observers and the 90,922 filters, using the database D1. For each observer, the filter that maximizes NODC has been chosen see . Table 1The relative variation of NODC for dataset D1 (ΔNODC) was small in all cases, on average 1.76% higher for dichromats than for anomalous trichromats. These relative variation data were similar to those reported by Linhares et al. . The facFor all observers, it should be noted that there were more filters that produced an increase in the NODC, even with minimal differences with respect to the selected filters. In For dichromats there was a higher relative number of filters that produce an increase in NODC, in comparison with anomalous trichromats. Neither of the two commercial filters studied produced an increase in NODC for any of the observers see . The samL*, a*, b* and the perceptual attributes Chroma (abC*) and hue (abh) were determined using datasets D1 and D2. Moreover, the shift caused by the filter on the color distributions of L*, a*, b* was also analyzed for both datasets. Once the filters that maximized NODC were selected for each simulated observer, the change that these filters produce on average on the color coordinates L*, a*, b* average shifts caused by the selected filters are shown for both datasets and each observer. The increments were computed by taking the unfiltered condition as reference.In As expected, lightness (L*) decreased when a filter was introduced since the filter partially absorbs the incident light and no lightness or chromatic adaptations were considered. The trends found for the a* and b* coordinates were similar for both datasets and each observer. This can be explained by considering that the filter shifts the color coordinates in the same direction for both datasets. For different observers, however, the shifts differed because the selected filters were different and the shifts introduced were not in the same direction.ab and hab shifts, different trends were found regarding the sign of the shift for both datasets. If the L*, a*, b* distributions were examined with and without the filter , without (red) and with the selected filter for each observer (blue). The distributions for the two commercial filters EnChroma and VINO are also shown for all observers. In The filters produced a shift in the a*, b* coordinates in all cases. This shift made it impossible for the normal observers to perform correctly when using the VINO filter. The reason for this was that the position of the center of the ring formed by the test samples in the a*-b* chart changed in the filtered condition. Hence, since the new center was not close to the origin, sorting by hue no longer produced correct results, because the reference for sorting the samples was the a* positive axis and in the filtered ring, there could be more than one sample with the same hue angle. For CVD observers, even the unfiltered sample ring was not centered in the origin, reflecting that they were unable to perform the sorting task correctly for either filtered or the unfiltered conditions. Only the normal observers with the EnChroma filter were able to perform correctly because the shift caused by the filter was not enough to disrupt the sorting process.In The FM100 evaluation parameters for the normal observers did not change when the selected filter was introduced, so the filter did not alter the ability of the normal subject to correctly sort the FM100 samples. Regarding the CVD simulated observers, SQR values increased slightly for the deutan type observers, and they increased considerably for the protan type observers. The filter was thus worsening the performance to a higher degree for the protan type subjects. As shown in In this study, simulations were carried out to determine which spectral filter maximizes the number of discernible colors (NOCD) for normal observers, as well as four different types of red–green CVD observers . Simulations were carried out using standard colorimetry for both normal and CVD observers. For this purpose, a set of 90,920 simulated filters (composed of single and double band-pass and notch filters) were studied, together with two measured commercial filters released as passive aids for CVD observers by the VINO and EnChroma companies.Results on the choice of filters showed that, in all cases, the type of filter that maximized the NODC was a double notch, except for the protanope dichromats which was a double band-pass. Nonetheless, variations in NODC were small (maximum of 2.84%), and oscillated around 0% when different reflectance datasets were used. Moreover, both the EnChroma Cx-65 and VINO O2 Oxy-Iso commercial filters were shown to decrease the NODC for all studied observers and reflectance datasets. In this regard, the single band-pass filters did not yield any NODC increase either.sRGB renderings from D2 and D3 were carried out for the five types of observers, both with and without a filter. In case of dataset D3: Ishihara, the chosen filters were shown not to include any improvement, which lead CVD observers to fail this test even when using these filters. On the other hand, results from FM100 test using these filters showed that CVD observers were unable to pass this test either, or even get close to the filterless performance of normal observers. FM100 seems to be the most reliable test for evaluating the efficacy of colored filters in color perception. Regarding the commercial filters, the EnChroma filter did not improve the performance of either the Ishihara test or the FM100 test, whilst the VINO filter helped CVD observers recognize the numbers in the Ishihara test but did not allow any observer  to pass the FM100 test.These results, assuming the limitations of using standard colorimetry for CVD observers, support the hypothesis that, even though some filters may slightly increase the number of discernible colors, they can never allow CVD observers to perceive colors more similarly to normal observers. Even normal observers can stop perceiving colors correctly when using some of these filters, and they become unable to pass the FM100 test. In the future, if new personalized colorimetry frameworks are developed, especially for CVD observers, it would be very interesting to compare the results obtained to quantify the effects of these filters with the ones presented in this article.


Data stewardship is an essential driver of research and clinical practice. Data collection, storage, access, sharing, and analytics are dependent on the proper and consistent use of data management principles among the investigators. Since 2016, the FAIR  guiding principles for research data management have been resonating in scientific communities. Enabling data to be findable, accessible, interoperable, and reusable is currently believed to strengthen data sharing, reduce duplicated efforts, and move toward harmonization of data from heterogeneous unconnected data silos. FAIR initiatives and implementation trends are rising in different facets of scientific domains. It is important to understand the concepts and implementation practices of the FAIR data principles as applied to human health data by studying the flourishing initiatives and implementation lessons relevant to improved health research, particularly for data sharing during the coronavirus pandemic.This paper aims to conduct a scoping review to identify concepts, approaches, implementation experiences, and lessons learned in FAIR initiatives in the health data domain.The Arksey and O’Malley stage-based methodological framework for scoping reviews will be used for this review. PubMed, Web of Science, and Google Scholar will be searched to access relevant primary and grey publications. Articles written in English and published from 2014 onwards with FAIR principle concepts or practices in the health domain will be included. Duplication among the 3 data sources will be removed using a reference management software. The articles will then be exported to a systematic review management software. At least two independent authors will review the eligibility of each article based on defined inclusion and exclusion criteria. A pretested charting tool will be used to extract relevant information from the full-text papers. Qualitative thematic synthesis analysis methods will be employed by coding and developing themes. Themes will be derived from the research questions and contents in the included papers.The results will be reported using the PRISMA-ScR  reporting guidelines. We anticipate finalizing the manuscript for this work in 2021.We believe comprehensive information about the FAIR data principles, initiatives, implementation practices, and lessons learned in the FAIRification process in the health domain is paramount to supporting both evidence-based clinical practice and research transparency in the era of big data and open research publishing.PRR1-10.2196/22505 Advancement in information communication technology is impacting the health ecosystem’s technological and analytical capabilities to store, curate, share, and analyze data from standard and nonstandard sources . In the Digitalization brings opportunities and concerns in health care data processing. Despite many potential benefits, it also poses potential threats, such as breaches of privacy, disinformation and misinformation, and cyberattacks . There iThe European GDPR is the most recent data regulatory framework as of September 2020 and has implications on the ethical sharing of research data . As the Boeckhout et al  highlighBeyan et al  have shoThe need for good data stewardship among different stakeholders in scientific research is the basis on which the FAIR data principles  were coined in 2014 by the FORCE11 (The Future of Research Communication and e-Scholarship) community ,19. ThesIn 2020, Vesteghem et al  outlinedThe aims for conducting this work are to (1) provide an overview of applications of the FAIR data principles that are focused on health data research and (2) map out the existing evidence accordingly.This scoping review will adopt the framework outlined by Arksey and O’Malley . The autWe have already conducted a pilot overview of the existing literature as an informal desk review and literature exploration. This overview included published works in PubMed, Google Scholar, and Web of Science. The medical and public health research librarian used the FAIR data principles’ keywords to match medical subject headings (MeSH) used to tag PubMed peer-reviewed literature, along with combinations of terms used in clinical research, public health, health care, pharmacology, and patient data. As part of the ongoing evidence synthesis from medical and human health research journal articles that used FAIR data markup, the bibliographies of key papers were scrutinized for other complementary publications, and those articles were added to the PubMed collections shared with the authors. Further, as the key FAIR data and health articles inspired new citations, often authored by similar consortia of writers or networks of researchers, the newer citing articles were added to the stage 1 collection to demonstrate possible progress in the field of shared or open medical data. Recurrent alerts were set up to capture newly published literature on PubMed, Google Scholar, and Web of Science . White pOur informal desk review has shown that many approaches used in the implementation of the FAIR data principles are applied to the life sciences domain . We haveAs we intend to conduct this exploratory review in an iterative manner, further refinement of the research questions may become necessary. Close examination of key references in bibliographies and citing articles to gauge the impact of shared data on ensuing research and health practice will be followed as part of the secondary analysis. All proposed refinements of the research questions and search methods will be scrutinized by the authors prior to approval. We will also provide comprehensive provenance information on changes in the protocol to be fully transparent.The general objective of this protocol is to conduct a scoping review to identify concepts, approaches, implementation experience, and lessons learned from the FAIR data principle initiatives in the health domain. The following research questions (RQs) have been formulated to meet the objective of the scoping review:RQ 1: What approaches are being used or piloted in the implementation of the FAIR data principles in the health data domain since the conception of these principles in 2014?RQ 2: What are the challenges and risks regarding the approaches used in the practical implementation of the FAIR data principles in the health data domain?RQ 3: What are the suggested concepts and approaches to mitigating the concerns of the implementation of the FAIR data principles in the health data domain?RQ 4: Which are the active public and private research and service networks involved in the implementation of the FAIR data principles in the health data domain?RQ 5: What are the reported outcomes for data sharing, data reuse, and research publication after the implementation of the FAIR data principles in the health data domain?With the aid of an experienced research librarian, at least two researchers will identify relevant studies from 3 primary electronic databases: PubMed, Web of Science, and Google Scholar. In addition to those, relevant grey literature from existing networks, relevant organizations, and conferences as well as the reference lists from potential papers will be searched. The keywords for the scoping review search strategies have been categorized tentatively to terms related to the FAIR data principles, data sharing, and health. Although refinement of the selected MeSH terms are possible, open terms have been proposed for the construction of the search strategy of this protocol. The Boolean operators “AND” and “OR” will be used to guide the search strategy. The following descriptors and keywords and their combinations were used to construct the strategies: “open science,” “data collection,” “data provenance,” “open access publishing,” “data*,” ”repositor*,“ ”registr*,“ ”pharma*,“ ”health*,“ ”research,“ ”biomedical research,“ ”data management,“ “FAIR data principles,” “FAIR principles,” “FAIR guiding principles,” “Data steward*,” “Data management systems,” “findable,” “findability,” “access,” “accessibility,” “interoperable,” “interoperability,” “reusable,” “reusability” .The PRISMA-ScR  reporting guidelines will be used for reporting the findings . The opeAs an inclusion criterion, we will consider literature published between January 1, 2014, and December 31, 2020. The start date in 2014 is chosen due to the fact that FAIR concept initiatives and official publications became first available in that year. Moreover, to be included as a potential paper, the literature needs to be published in English and include the scope of FAIR principle applications in the health domain . Literature published before 2014, in a language other than English, and in domain areas other than health or the operational definition of health will be excluded. All search results from online databases and grey literature sources will be exported to a reference management software to eliminate duplications. Unique search results will be exported to a screening tool to facilitate an independent screening process for the potential papers.Rayyan software (Qatar Computing Research Institute) has been chosen as the primary screening and data extraction tool to expedite the initial screening of abstracts and titles using a semiautomated process while incorporating a high level of usability. This software supports research teams in the easier exploration of literature searches within a shorter time as well as in sharing and comparing individual researchers’ decisions to include or exclude studies . AccordiA data-charting form will be used by the reviewers to determine which variables to extract. The form is flexible for continuous updating in an iterative manner during the data-charting process, but any changes will be tracked. The descriptive analytical approach, as described by Arksey and O’Malley , will beThis scoping review focuses on the range of data curated and the health data research content identified. Quantitative assessment is limited to a count of the number of sources reporting a particular FAIR thematic issue or recommendation. After charting the relevant data from the studies in spreadsheets, the results will be collated and described using summary statistics, charts, figures, and common tools for analytical reinterpretation of the literature . MappingOur PubMed preliminary search has yielded 360 results . The seaThis scoping review will provide insight on the initiatives, concepts, and implementation practices of FAIR data principles in health data stewardship. More specifically, it will allow for the exploration of (1) approaches being used or piloted for the implementation of the FAIR data principles in the health domain since the conception of these principles in 2014; (2) challenges, risks, lessons learned, and the suggested concepts and approaches to mitigate the concerns of implementation of the FAIR data principles in the health domain; (3) active research and service networks involved in the implementation of the FAIR data principles in the health domain; and (4) the reported outcomes for data sharing, data reuse, and research publication after the implementation of the FAIR data principles in the health domain. We anticipate increases in data repositories demanding FAIR data markup suitable for artificial intelligence extraction of statistics. We also anticipate a greater demand for the implementation of the FAIR principles in light of the ongoing COVID-19 pandemic as well as more open research activities by public and private research and service networks involved in the implementation of the FAIR data principles in the health domain. An example of such an initiative is the Research Data Alliance .The results will be used to generate recommendations on how to integrate the FAIR principles in health research, and we will generate different knowledge dissemination materials to share project results with various stakeholders, partners, associations, and networks who may benefit from this work.The findings of this proposed work may be used to help identify the types of available evidence that support the incorporation of FAIR data principles in health. The results will also help to clarify key concepts in the scientific literature and serve as an introduction to how research on FAIR practices is conducted. This methodological framework will help us identify the overall state of research activities that explore initiatives, concepts, and implementation practices of FAIR data principles in health data stewardship. The outcome of this review can be used to further determine areas of research based on current gaps in the literature. Conducting this scoping review will also help determine the practicality and relevance of a full systematic review on the same issues by assessing the availability of literature. Similarly, gaps that still exist in the uptake and implementation of the FAIR principles in health research will also be identified as areas of further research. This work will be of interest to various stakeholders, including health and academic institutions, publishers, researchers, and funding agencies. In the wake of the COVID-19 pandemic, it is extremely critical that health data stewardship is practiced in a FAIR manner to facilitate the globally coordinated response . As thisOnce complete, this work will be published in a peer-reviewed journal, and the results will also be presented at appropriate forums or conferences. Ethical approval is not required, as only secondary data from published sources will be included in the scoping review and the public is not invited to participate in this work.


MCA1 and MCA2 genes, and the growth of hypocotyls of mca mutants, under hypergravity conditions in the dark. An MCA1 promoter::GUS fusion reporter gene construct (MCA1p::GUS) and MCA2p::GUS were expressed almost universally in etiolated seedlings. Under hypergravity conditions, the expression levels of both genes increased compared with that under the 1 g condition, and remained higher, especially in the basal supporting region. On the other hand, mca-null and MCA-overexpressing seedlings showed normal growth under the 1 g condition. Hypergravity suppressed elongation growth of hypocotyls, but this effect was reduced in hypocotyls of mca-null mutants compared with the wild type. In contrast, MCA-overexpressing seedlings were hypersensitive to increased gravity; suppression of elongation growth was detected at a lower gravity level than that in the wild type. These results suggest that MCAs are involved in the perception of gravity signals in plants, and may be responsible for resistance to hypergravity.Plants respond to and resist gravitational acceleration, but the mechanism of signal perception in the response is unknown. We studied the role of MCA (mid1-complementing activity) proteins in gravity perception by analyzing the expression of the  Plants are exposed to a variety of mechanical stresses such as wind and gravity, and they have developed efficient mechanisms to respond to these stressors over evolutionary time, in particular after their emergence on land. We have previously studied the mechanisms of plant responses to gravitational acceleration, mainly with basipetal hypergravity produced by centrifugation ,2. Hyperg, and hypergravity did not affect these factors when the gadolinium ions were present [The mechanism of gravity signal perception in the response of plants to hypergravity has been examined. Gadolinium ions, blockers of mechanosensitive ion channels ,11, null present . These r present . Howevermid1 mutant, which lacks a putative Ca2+-permeable mechanosensitive channel [2+ influx in yeast cells and Arabidopsis seedlings [2+ concentration [Xenopus laevis oocytes [2+ and cold tolerance [MCA1 and MCA2 genes, and the growth of etiolated hypocotyls of mca mutants, under hypergravity conditions.Candidates for the mechanosensitive ion channels have been reported in Arabidopsis; MCA (mid1-complementing activity) proteins are one such candidate. The amino acid sequences of the MCA1 At4g35920) and MCA2 At2g17780) proteins share 73% homology and partially complement the yeast  channel ,16. Both channel ,17. Mult780 prote channel . MCA1 aneedlings ,16, a hyntration ,18, and  oocytes . Both pr and MCA2MCA1 and MCA2 in etiolated seedlings grown at 300 g were analyzed using an MCA1 promoter::GUS fusion reporter gene construct (MCA1p::GUS) and MCA2p::GUS. MCA1p::GUS was expressed in the cotyledons and hypocotyls, regardless of age or gravitational conditions  was normal in the dark at 1 g  in the MCA1- and MCA2-overexpressing mutants  [g hypergravity on growth and the cell wall were restored when the plant materials were transferred to 1 g conditions, and were completely nullified by the presence of gadolinium ions, as mentioned above. These results indicate that hypergravity at 300 g is not an extraordinary stimulus for plants, and that the plant response to this magnitude of gravity stress is within the normal physiological limits. However, the role of MCAs in the perception of gravity signals at 1 g has yet to be determined. For this purpose, analyses under true microgravity conditions in space may be most effective as the control; a space experiment termed plant gravity sensing (PI: H. Tatsumi) is now underway.Here, we analyzed changes in the expression of mca1-null, mca2-null, mca1-null mca2-null, MCA1-overexpressing, MCA2-overexpressing, MCA1p::GUS, and MCA2p::GUS were used in this study. The details of these lines have been previously described [w/v) agar in a 50 ml centrifuge tube, incubated at 4 °C in the dark for 4 days, and then exposed to light  at 23 °C for 1 day to induce germination. After germination, the seeds were incubated at 25 °C in the dark for 1 day. Hypergravity experiments were conducted as reported previously [g  at 25 °C for 1 day in the dark. After treatment, the lengths of the hypocotyls were measured using a scale. The suppression ratio was calculated as a ratio (percentage) of the difference between the elongation under 1 g and the hypergravity conditions to the 1 g value. Because the lengths of hypocotyls at 1 g were different from line to line, the elongation growth data were compared between the 1 g and hypergravity treatments in each line and analyzed with Student’s t-test , 0.1 M sodium phosphate buffer, pH 7.0, 0.5 mM potassium ferrocyanide, and 0.5 mM potassium ferricyanide) after infiltration with a vacuum pump for 1 h. The stained seedlings were fixed in a mixed solution (ethanol: acetic acid = 3:1) for 5 h, washed stepwise with 70%, 50%, and 20% ethanol for 10 min each, and cleared overnight at 4 °C with a cleaning solution . Quantification of the GUS-staining intensity of each region of the hypocotyl was performed using ImageJ, as reported previously [t-test.Seedlings were fixed in 90% acetone in the dark for 1 h and washed twice with 0.1 M sodium phosphate buffer, pH 7.0. The seedlings were then incubated at 37 °C for 20 h with X-Gluc buffer (0.5. mg mLeviously . The GUSg gravity by space experiments.MCA1 and MCA2 are at least partly involved in gravity perception when Arabidopsis hypocotyls are exposed to hypergravity. These genes may be responsible for gravity signal perception in the gravity resistance of plants. Future studies should examine the involvement of MCA proteins in plants’ resistance to 1


RFI) or residual feed intake and body weight gain (RIG) exhibit differences in thermography, blood, and ruminal parameters. Thirty-two Gyr heifer calves were enrolled in a 63-d trial and classified into 2 feed efficiency (FE) groups based on RFI and RIG (mean ± 0.5 SD). The groups were classified as high efficiency (HE) RFI , HE RIG , low efficiency (LE) RFI , and LE RIG . The amount of whole milk provided for each calf was calculated based on their metabolic weight at birth (42% x BW0.75). The liquid diet was divided into two meals at 0700 and 1400 h. The total solid diet (TSD) was composed of 92% concentrate and 8% of Tifton 85 hay chopped in 5-cm lengths, as fed. Intake was measured daily. Blood concentrations of insulin, beta hydroxybutyrate, urea, and glucose, and ruminal pH, N-NH3, and volatile fatty acids (VFA) were evaluated at 14, 28, 42, 56, and 70 days of age. Thermal images of the calves were taken with an infrared camera  on d 56 (±3) at 0600 h, before the morning feeding. Total VFA concentration and propionate as % of total VFA were 24.2% and 22.2% lower in HE RFI compared to LE RFI calves, respectively. On the other hand, acetate as % of total VFA was 10.6% greater in HE RFI than LE RFI calves. Blood urea concentration tended to be greater in LE RFI than HE RFI calves. High efficiency HE RIG tended to have 6.8% greater acetate and 15.4% lower propionate as % of total VFA than LE RIG. Blood insulin concentration was greater and blood glucose tended to be greater for LE RIG than HE RIG group. Low efficiency RIG group had greater left rib, left flank, and anus surface temperature measured by infrared thermography than the HE RIG group. Differences in ruminal fermentation do not seem to be associated with pre-weaning calves efficiency, while differences in protein metabolism seem to affect RFI during this phase. Infrared thermography appears to be correlated to RIG in pre-weaning heifer calves.The objective of this study was to evaluate whether pre-weaning heifer calves divergent for residual feed intake ( FE) is essential to increasing profitability [RFI) is a FE index calculated as the difference between actual and expected animal feed intake, at a certain level of production [In milk production systems, feed corresponds to 50% of the total cost of production ; therefotability . Feed eftability . More spoduction . The indoduction .Some studies linked RFI during lactation with RFI during the growth phase, indicating that RFI may be a lifetime trait ,8. UnderRIG) was proposed as an alternative index to select efficiently growing animals. In a companion paper [The selection of slow-growing animals can be a problem associated with RFI ; thus, ron paper , we detaTo our knowledge, no research has been conducted to evaluate the possible differences in ruminal and blood metabolites in groups divergent for FE indexes in pre-weaning dairy calves. Moreover, while research conducted by our investigative group concluded that thermography may have the potential to be used for screening phenotypical divergence in calves classified for residual body weight gain , no compThis study was approved by the Ethics Committee of Embrapa Dairy Cattle (number: 7194210316). The study was conducted at the Farm of Embrapa Dairy Cattle, located in Coronel Pacheco, Minas Gerais, Brazil.As stated above, the data presented in this paper is part of a study that classified calves into high and low feed efficiency groups using two feed efficiency indexes (RFI and RIG). A detailed description of methods, diets composition, performance data, calculation of indexes, and group classifications are provided in . Brieflyth to the 77th day of age divided into 2 equal meals offered at 0700 and 1400 h in nipple buckets . On the 78th day of age, milk supply was reduced by half, and the heifer calves were weaned on the 81st day of age. Water and total solid diet  were offered ad libitum in buckets . Milk samples were collected twice daily (morning and afternoon) and analyzed for total solids, crude protein, lactose, and fat. The solid diet was provided since the first day of life and composed of 92% starter  and 8% Tifton 85 (Cynodon spp.) hay chopped in 5-cm lengths, as fed. Samples of the TSD were collected 3 times a week, and composited and homogenized weekly.The amount of milk offered for each calf was 42% of their metabolic weight at birth. The mean weight of calves at birth was 25.2 ± 3.2 kg (mean ± SD). Consequently, the daily milk supply was 4.7 ± 0.46 L. Calves received transition milk until 3 days of age, and whole milk from the 4Individual refusals were collected daily and were composited weekly. Milk, TSD, and water intake were measured individually. Daily intakes of milk, TSD, and water were calculated by the difference between offers and refusals. Feed and water were weighed using a bench scale  and a portable scale , respectively. Body weight was recorded before the morning meal on days 3 and 7 after birth, and weekly from day 8 onward.th to the 77th day of age to calculate the indexes based on 63 days of observation [ADG) of each animal. Mean daily feed intake was calculated for each animal over the trial period and corrected for DM. The average metabolic weight (BW0.75) was calculated using the BW at the 46th day of age, which was the middle of the test period.Solid feed was offered since the first day of life, but feed efficiency evaluations started with 14 d of age since there was no expressive solid intake before this age. Intake and performance were evaluated from the 14ervation . The gro0.75, and ADG were used to estimate RFI and residual body weight gain (RG) using linear regressions [0.75, β2 is the regression coefficient for ADG (RFI) or DMI (RG), and ej is the error term for calf j. In the present study, RG was not used as an FE index. The RG calculation was performed to estimate RIG. To calculate RIG, the residues for RFI and RG were added as [Dry matter intake, BWressions , where Radded as :RIG=[RFHE) and low efficiency (LE) for RFI and RIG. HE indicated RFI < 0.5 SD below the mean (n = 9) and RIG > 0.5 SD above the mean (n = 10), while LE indicated RFI > 0.5 SD above the mean (n = 10) and RIG < 0.5 SD below the mean (n = 11). The remaining animals were classified as intermediate and were not included in subsequent analyses.Based on these indexes, the animals were classified into four groups: high efficiency (BHB), urea, and glucose, blood samples were taken at 14, 28, 42, 56, and 70 days of age; to determine the concentration of insulin, blood samples were taken at 28, 42, 56, and 70 days of age. All blood samples were taken via venipuncture of the jugular vein, 3 h after the morning meal. Tubes without anticoagulant for insulin, BHB, and urea, and with fluoride EDTA for glucose  were used. The tubes were stored on ice until centrifugation at 1,800 × G for 10 min at room temperature (22–25°C).To determine the concentration of beta hydroxybutyrate . Insulin was analyzed using a Bovine ELISA kit . The coefficients of inter- and intra-assay variation were 11.2% and 9.1%, respectively. BHB determination was performed using an enzyme kinetic kit . All readings were performed on an EON microplate spectrophotometer .Ruminal fluid samples were collected at 14, 28, 42, 56, and 70 days of age using an esophageal tube, 3 h after morning feeding. The liquid was double filtered through cheesecloth, and pH was measured .3 determination, 5 mL of filtered ruminal liquid was acidified with 1 mL of sulfuric acid (500 mL/L) and stored at −20°C until further analysis. Analyses were performed after distillation of Kjeldahl with magnesium oxide and calcium chloride according to method 920.03 [VFA) determination, 1 mL of 20% metaphosphoric acid was added to 10 mL of filtered ruminal liquid and stored at −20°C. Samples were defrosted at room temperature (22–25°C) and centrifuged at 13,000 rpm for 10 minutes. The samples were analyzed by high performance liquid chromatography .For N-NHd 920.03 . For volThermal images of the calves were taken with an infrared camera  on day 56 (±3) at 0600 h, before the morning feeding. The standard distance between thermograph and the target anatomical region was 0.5-m. The FLIR T420 default settings values for emissivity (0.98) and reflectance temperature (20ºC) recommended for animal skin or watery surface (eye) were used . All theTo establish a constant area of evaluation, a figure was drawn on the image surface, and it was then dragged to the region of the skin located in the chosen area . Only thijk is the dependent variable, β0 is the intercept, β1Aij is the regression coefficient for the covariate initial BW, β2Bij is the regression coefficient for the covariate total serum protein, Gi is the fixed effect of efficiency group (RFI or RIG), Mk is the fixed effect of repeated measure (day or week), GMik is the fixed effect of interaction between group and repeated measure, δij is the random error between animals within treatment, and εijk is the random error between measurements within animals. The best covariance structure for repeated measures was chosen by the lower corrected Akaike information criteria (AICc). For significative interaction between group and repeated measure, the differences among groups within measures were evaluated using the SLICE statement. For thermography data, the effects of repeated measures and its interaction with treatment were not included in the model and one random error term was used. Significance of the effects was declared at P ≤ 0.05, and tendency was accepted when 0.05 ≤ P ≤ 0.10.Statistical analysis was performed using SAS software . To evaluate the effects of efficiency in the groups, the MIXED procedure was used, according to the model:P < 0.01). The HE RFI consumed 8.9% less than the LE RFI group. Total intake was 0.76 and 0.84 kg/d for the HE and LE RFI groups, respectively . Average daily gain was 0.60 and 0.59 kg/d for the HE and LE RFI groups, respectively , and body weight was 48.2 and 46.6 for the HE and LE RFI groups, respectively  [Average RFI for the HE group was −0.052 kg/d, and for the LE group, it was 0.049 kg/d  were observed for ruminal pH, N-NH3 concentration (%), and proportion of butyrate (%VFA) between HE and LE RFI groups (P = 0.001) for LE than HE RFI group. In addition, propionate (%VFA) was greater in the LE RFI group (P = 0.002), while acetate (% VFA) was lower for this group (P = 0.01).No statistical differences . Low efficiency RFI group had greater ruminal VFA concentrations at 28 and 42 d of age in comparison to HE RFI group . Acetate concentration was lower in the LE RFI group at 28 and 42 d of age, while propionate concentration was greater in the LE than in the HE RFI group at 28, 42, and 56 d of age  (P = 0.06) to be greater in LE than HE RFI group.Blood BHB, glucose, and insulin concentrations did not differ between RFI groups ( > 0.22) . Blood uP = 0.048) between flank temperature and RFI was observed . Average daily gain was 0.60 and 0.55 kg/d for the HE and LE RFI groups, respectively , and body weight was 47.8 and 46.3 for the HE and LE RFI groups, respectively  [The average RIG for the HE group was 0.080 kg/d, and for the LE group, it was −0.077 kg/d. The HE RIG group had an 8.6% greater ADG than the LE RIG group . Total i< 0.001) .P = 0.08) and a lower proportion of propionate (%VFA) (P = 0.06) concentrations in HE RIG compared to LE RIG group.No differences in ruminal parameters between the HE and LE RIG groups were observed , except P = 0.02) for LE than for HE RIG group (P = 0.06) to be greater in the LE RIG group compared to the HE RIG group, but no differences in BHB and urea between RIG groups were observed. In addition, a treatment × week interaction for blood insulin concentration was observed (P = 0.001). Insulin was greater in LE compared to HE RIG animals at 56 days of age (Blood insulin concentration was greater (IG group . Blood gs of age .P = 0.03) left rib, left flank, and anus surface temperature measured by infrared thermography compared to the HE RIG group (P = 0.005) and rib temperature  with RIG were observed.The LE RIG group had greater  exhibit differences in thermography, blood, and ruminal parameters. Clear evidence of differences in these parameters when using RFI or RIG as indexes for calves was observed for proportions of acetate and propionate in rumen VFA, blood glucose, insulin and urea depending on the FE index evaluated. The results also indicated differences in body surface temperatures when the calves were classified based on RIG but not RFI. Results from the current study indicates divergences on physiological basis underlying RFI and RIG and opens the perspective for future studies on a better understanding of how these differences affect productive traits of lactating dairy animals. Complementary results on performance body measurements, digestibility, energy partitioning, and nitrogen partitioning were described by .Residual feed intake is defined as the difference between observed and expected feed intake based on the requirement to support both maintenance and growth . High-ef3 between RFI groups were observed. Other studies that also used esophageal tube did not find differences in ruminal pH between HE RFI and LE RFI [No differences in pH and N-NHd LE RFI ,18, demoIn the present study, calves with greater solid intake (LE RFI group) also had greater total VFA (μmol/mL). Similar results were also observed in LE RFI animals under feedlot conditions fed a grain-based diet . Since rDifferences in ruminal fermentation do not seem to be associated with pre-weaning calves' efficiency. A possible reason why HE RFI group kept the same ADG eating less and with lower VFA concentration may be related to more efficient post-ruminal digestion and absorption of nutrients in that group. Data from the same study presented in companion paper already published , showed P < 0.10) for greater insulin in the LE RFI groups [Blood concentration of metabolites and hormones can be a useful tool to understand differences in metabolism. Several RFI studies have evaluated blood parameters to understand differences in feed efficiency and tried to detect potential physiological markers for FE ,23. In tI groups  or a weaI groups .In young ruminants, the main contribution to the plasma concentration of butyrate is related to its production in the rumen . TherefoLow-efficiency RFI group tended to have greater blood urea concentrations in comparison to the HE RFI group. An association between greater concentrations of blood urea and LE RFI has been previously reported in the literature ,27. ThisPrevious studies reported correlations between heat production and skin surface temperature measured by infrared thermography ,30. SincResidual feed intake and body weight gain were proposed to be an intermediary index between RFI and RG . Hence, As discussed above for RFI, changes in VFA concentration and percentage of each VFA followed intake parameters. The tendency to greater availability of fermentable substrate in rumen appears to be responsible for the tendency of greater molar concentrations of VFA in LE RIG compared to HE RIG group. In addition, the tendency to greater ruminal propionate  and acetate  proportion in LE RIG compared to HE RIG may be related to differences in passage rate between the groups.The LE RIG group had greater blood insulin concentration at 56 d of age and tended to have greater glucose concentration. The secretion of insulin depends on the rate of nutrient absorption in the small intestine, feed composition, and neuroendocrine signaling to the pancreas . Low-effAs mentioned before, one of our hypotheses was that HE RIG animals would dissipate less heat through the skin, reflecting lower heat production due to a possible more efficient metabolism. Although LE RIG animals had a greater left rib, left flank, and anus surface temperatures compared to HE RIG measured by infrared thermography, no differences in heat production measured by respiration chamber, presented in the companion paper , betweenThese results do not corroborate with our initial hypothesis that skin surface temperature would reflect differences in heat production between HE and LE RFI groups; however, moderate correlations between surface temperature in some regions and RIG were observed. It is not clear which mechanism links greater efficiency and lower skin surface in RIG groups. Thus, more research is needed to investigate the relationship between RIG and skin surface temperature measured by thermography.Total ruminal VFA concentration and the proportions of acetate and propionate  were greater in the LE RFI and RFI groups. Therefore, ruminal fermentation does not seem to be associated with pre-weaning heifer calves FE. Blood urea concentration was greater in the LE RFI group, suggesting protein metabolism as a possible key point determining differences in FE in pre-weaning dairy calves. Infrared thermography seems to be correlated to RIG but not to RFI; however, the mechanism linking skin surface temperature to RIG is not clear. This study indicates differences in physiological basis underlying RFI and RIG; therefore, more research needs to be conducted to better understand how these differences can affect the productivity of lactating cows and which index has better potential to improve the selection of more efficient animals.S1 Database(XLSX)Click here for additional data file.


Lactobacillus fermentum CQPC04. The in vivo results indicated that L. fermentum CQPC04-fermented soy milk enhanced the organ index of the liver and spleen, and improved the pathological morphology of the liver, spleen, and skin. L. fermentum CQPC04-fermented soy milk increased the enzymatic activity of glutathione peroxidase (GSH-Px), total superoxide dismutase (T-SOD), and catalase (CAT), increased glutathione (GSH), but decreased the levels of nitric oxide (NO) and malondialdehyde (MDA) in serum, liver, and brain tissues of oxidative aging mice. The above mentioned fermented soy milk also increased the levels of collagen I (Col I), hyaluronic acid (HA), and collagen III (Col III), and decreased the levels of advanced glycation End products (AGEs) and hydrogen peroxide (H2O2). The RT-qPCR results showed that L. fermentum CQPC04-fermented soy milk upregulated the mRNA expression of nuclear factor erythroid 2?related factor (Nrf2), heme oxygenase-1 (HMOX1), quinone oxido-reductase 1 (Nqo1), neuronal nitric oxide synthase (NOS1), endothelial nitric oxide synthase (NOS3), Cu/Zn–superoxide dismutase (Cu/Zn-SOD), Mn–superoxide dismutase (Mn-SOD), and CAT, but downregulated the expression of inducible nitric oxide synthase (NOS2) and glutamate cysteine ligase modifier subunit (Gclm) in liver and spleen tissues. Lastly, the fermented soy milk also increased the gene expression of Cu/Zn-SOD, Mn-SOD, CAT, GSH-Px, matrix metalloproteinases 1 (TIMP1), and matrix metalloproteinases 2 (TIMP2), and decreased the expression of matrix metalloproteinase 2 (MMP2) and matrix metalloproteinase 9 (MMP9) in skin tissue. In conclusion, L. fermentum CQPC04-fermented soy milk was able to satisfactorily delay oxidative aging effects, and its mechanism may be related to the increase in free soy isoflavones and peptides.The aim of this study is to evaluate the changes in soy isoflavones and peptides in soy milk after lactic acid bacterial fermentation, and explore the positive effects of fermented soy milk on an oxidative aging mouse model induced with D-galactose. We found that free soybean isoflavones and peptides increased after soy milk was fermented by  The United Nations (UN) predicted that there would be an average annual increase rate of 2.5% in the elderly population from 1990 to 2020, and over the same period, the proportion of the world's aging population has risen from 6.6% in 1995 to 9.3% in 2020  (ABTS), 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH), and hydroxyl  under accession number CGMCC 14493, and this strain was originally isolated from pickles in Chongqing, China by our group.ad libitum. All of the experiments were was performed according to 2010/63/EU directive and national standard of the people's Republic of China (GB/T 35892-2018) laboratory animal-guidelines for ethical review of animal welfare and institutional rules considering animal experiments. At the same time, the study protocol was approved by the Ethics Committee of Chongqing Collaborative Innovation Center for Functional Food .Fifty 7-week-old female ICR mice were purchased from Chongqing Byrness Weil Biotech Ltd. . The mice were maintained in a room at constant temperature and humidity  with 12 h of light and 12 h of darkness, and they were allowed to ingest standard mouse chow and water L. fer mentum CQPC04 with a viability count of 1.0 × 105 CFU/mL was added to sterilized soy milk, and then put in a constant temperature incubator  for fermentation, the fermentation condition is 37°C, 12 h. The final viability count in the fermented soy milk was 1.3 × 108 CFU/mL.According to a previous method with modification , L. fer The soy isoflavones in soy milk were analyzed by HPLC . Based on a previously published method with slight adjustments , 15 mL oAccording to a previously described protocol , the proL. fermentum CQPC04-fermented soy milk group , and (v) D-galactose + non-fermented soy milk group . The groups and their specific treatments for the entire experimental period are presented in After adaptive feeding for 1 week, fifty female Kunming mice were equally distributed into five groups, consisting of the (i) normal group, (ii) D-galactose group , (iii) D-galactose + vitamin C group , (iv) D-galactose + All mice were fasted with water for 16 h and depilated on the back before being euthanized by severing the spinal cord. Whole blood was collected and centrifuged at 4,000 rpm for 10 min at 4°C to obtain the upper serum. Then, the liver, spleen, and whole brain were weighed to calculate the organ indexes. The organ indexes were determined by the following formula: C (%) = (m1/m2) × 100, in which C represents the organ index, m1 denotes the organ weight, and m2 denotes the body weight of the mice.Soybean-sized pieces of tissue of the liver, spleen, and skin were harvested and fixed in 10% paraformaldehyde solution for 48 h. Then all of the above tissues were delivered to Wuhan Sevicebio Biotechnology Co., Ltd.  for pathological detection. Lastly, an upright microscope  was used to observe the morphology of the tissues and obtain photographs.The levels of GSH-Px, GSH, T-SOD, MDA, NO, and CAT in serum were directly determined using conventional biochemical kits and following the manufacturer's instructions . In addition, it was necessary to pre-treat the mouse liver and brain tissues before measuring the above indicators, which consisted of homogenizing one gram of tissue and 9 mL of physiological saline with a tissue homogenizer , centrifuging the homogenate at 12,000 rpm for 10 min at 4°C, and collecting the supernatant as the measurement sample for the above indicators.The skin pretreatment method used was same as that described in Section Measurement of Oxidative Indicators. The amount of hydrogen peroxide in the skin was determined using conventional biochemical kit , and Col I, AGEs, Col III, and hyaluronic acid levels were measured by the enzyme-linked immunosorbent assay (ELISA) kits .ΔCT−Δ, in which β-actin was chosen as the internal reference marker . Then, the mRNA was reverse transcribed into cDNA using a cDNA kit . Finally, RT-qPCR (reverse transcription-quantitative polymerase chain reaction) was performed, and a real-time fluorescence quantitative PCR instrument  was used to detect the mRNA expression of target genes. All primers were from Invitrogen , and their sequences are listed in e marker .p < 0.05 indicates statistical significance.Graph Pad Prism 7.0 and SPASS 17.0 software were used to calculate and analyze results, and the results presented as the mean ± standard deviation . L. fermentum CQPC04 (p < 0.05). The above results indicate that fermentation with L. fermentum CQPC04 can convert the macromolecular proteins in soy milk into small-molecule peptides.The peptide content and protein profiles are two useful indicators that can reflect the changes in the protein in soy milk before and after fermentation . From FiL. fermentum CQPC04-fermented soy milk, in which the organ indexes in the D-gal + CQPC04 group increased more than those in the other two groups and were similar to those of the normal group.There is usually degeneration or atrophy of organs during aging. As shown in L. fermentum CQPC04-fermented soy milk groups all displayed an increase in the percentage of white pulp to varying degrees. Moreover, the most white pulp was observed in the D-gal + CQPC04 group, which is similar to the normal group.The histological features of the spleen sections stained with H&E are presented in L. fermentum CQPC04-fermented soy milk, in which there was a more pronounced effect from the L. fermentum CQPC04-fermented soy milk as compared to the other groups.The aging of the skin is the most visible and obvious manifestation of organismal aging. H&E, Masson, and toluidine blue stains are usually used to observe pathological features of the skin. In the D-gal group, the skin dermis thickness  and collp < 0.05), which indicated a decrease in the anti-oxidative capacity of the mice. It is worth noting that L. fermentum CQPC04-fermented soy milk notably enhanced the levels of GSH-Px, T-SOD, GSH, and CAT, and reduced MDA and NO (p < 0.05). Additionally, there was no obvious difference in these indicators between the normal group and the D-gal + CQPC04 group (p > 0.05).Anti-oxidant enzymes, MDA, GSH, and NO can reflect the oxidative stress levels of aging mice induced by D-galactose. L. fermentum CQPC04-fermented soy milk on D-galactose-induced aging mice, we measured the amounts of AGEs, hyaluronic acid, Col I, hydrogen peroxide, and Col III in skin tissues .The RT-qPCR results indicate that the expression trend of related genes in the liver and spleen is consistent . The expCu/Zn-SOD, Mn-SOD, CAT, GSH-Px, tissue inhibitor of metalloproteinase (TIMP)1, and TIMP2 was the lowest, while that of matrix metalloproteinase (MMP)2 and MMP9 was the highest in the D-gal group. Compared with the D-gal group, the expression levels of Cu/Zn-SOD, Mn-SOD, CAT, GSH-Px, TIMP1, and TIMP2 increased, but MMP2 and MMP9 decreased in the D-gal + VC, D-gal + NO, and D-gal + CQPC04 groups. It is worth noting that the mouse skin in the D-gal + CQPC04 group possessed the highest mRNA expression levels of Cu/Zn-SOD, Mn-SOD, CAT, GSH-Px, TIMP1, and TIMP2, and the lowest expression levels of MMP2 and MMP9 except for the normal group, which demonstrated that L. fermentum CQPC04-fermented soy milk reduced the oxidant aging of skin and decreased the degradation of collagen fibers.Antioxidant enzymes and matrix metalloproteinases are important indicators that can be used to evaluate the degree of skin aging. As shown in L. fermentum CQPC04 to ferment soy milk and evaluated the changes in isoflavones and peptides, as well as explored the antioxidant effect of this fermented soy milk due to its antioxidant action.Soy milk fermented with lactic acid bacteria is beneficial to human health because of the bioactive components in the milk that play important roles. Studies have proved that using lactic acid bacteria to ferment soy milk can convert the conjugated isoflavones and proteins into aglycone isoflavones and bioactive peptides, respectively, which increases the bioavailability of these substances in the human intestinal tract . At presL. plantarum CQPC02 (7.59 μg/mL) were obviously higher than those of non-fermented soymilk (4.01 μg/mL) and fermented soymilk with Lactobacillus bulgaricus (4.05 μg/mL)  . Anotheroflavone . Our expL. fermentum CQPC04-fermented soy milk, and resulted in the high organ index of the liver and spleen, a return to the normal structure of the liver, spleen, and skin, as well as increased collagen fibers and few mast cells in the skin.With increasing age or as the aging process accelerates, the body's organs and tissues will gradually undergo changes such as atrophy and functional degradation. Our study found that the organ indexes of the liver and spleen was significantly decreased, and the histopathological morphology of the liver, spleen, and skin was damaged to varying degrees in mice, which showed that the anti-oxidative aging model was successfully established . In contL. sakei K040706, which is from traditional Korean fermented soybean paste, increased the spleen indices of cyclophosphamide-induced immunosuppressed mice   . A previing mice .2O2 will cause cytotoxicity to the skin, and lower amounts of HA can lead to reduced moisture, the presence of roughness and wrinkles, and a loss of skin elasticity  and also complied with the 2010/63/EU directive.XZho and H-hD performed the majority of the experiments and wrote the manuscript. MJ, CZ, and YD contributed to the data analysis. XZha and XL designed and supervised the study and checked the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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General linear models were used to study the associations between origin and mental health, comparing Ethiopian and FSU origin with native-Israeli. Ethiopian and FSU mothers were more likely to report on somatic symptoms, compared with native-Israeli women. Ethiopian origin was negatively and significantly associated with anxiety in all three interviews . FSU origin was negatively associated with depression after birth , and negatively associated with anxiety after birth and one-year postpartum . Stressful life events were significantly associated with all mental disorders in the three time points of interviews. Our findings suggest that immigrants tend to express higher mental distress with somatic symptoms. Additional tools are needed for mental distress screening among immigrants.We conducted a prospective study, aimed to study whether the prevalence of mental disorders after birth differs by country of origin. Parturient mothers of Ethiopian origin, Former-USSR (FSU) origin, or nonimmigrant, native-Israeli origin ( Postpartum depression (PPD) is the most studied mental disorder in women after delivery. It is considered the most common complication women experience after delivery, affecting about 13% of mothers worldwide (range: 10–25% across countries) . Over thRates of prenatal and postpartum depression were found to be especially high among immigrant populations in several countries ,13,14. AOne of the major problems in assessing the prevalence of PPD and anxiety across cultural settings relates to differences in definitions and expression of symptoms. Some studies have suggested that patients from non-Western cultures or developing countries are more likely to report somatic symptoms and deny psychological symptoms, especially if they are from Asian, African, and Hispanic cultures ,26. EthiOur hypothesis was that manifestations of postpartum mental disorders differ between immigrants and native-born in Israel according to different mental scales. Therefore, we aimed to study the different manifestations of mental disorders in parturient women from three origin groups, namely women of Ethiopian origin (ETH), Former Soviet Union origin (FSU) and native Israeli-born (INB) in a prospective study designed in three waves. Our assumption was that immigrant groups would have an increased prevalence of PPD, anxiety and somatic symptoms, and that there may be a different expression of mental morbidity after delivery among immigrants.We conducted a three-step study of mothers. Mothers were recruited after birth in 3 different hospitals in Israel  between April and December 2017 and were followed for one year. The study included women older than 18 years who were capable of understanding and completing questionnaires  in the postpartum period. The study population included 964 mothers: 484 Israeli-Native-born mothers, 264 Former-USSR origin mothers (212 first generation and 52 second generation immigrants) and 216 Ethiopian origin mothers (191 first generation and 25 second generation immigrants). After delivery, participating women answered an anonymized self-administered questionnaire that included questions about socioeconomic conditions, age, smoking habits, alcohol consumption, living with a spouse and type of delivery. Six to eight weeks after delivery and again after twelve months, the women were re-interviewed by phone. Anxiety and depression were assessed by completing the General Anxiety Disorder 7 Item Scale (GAD-7) and the Edinburgh Postnatal Depression Scale (EPDS), respectively. Seven questions from the SRQ-F questionnaire (the Revised Self-Reporting Questionnaire for Ethiopian origin population) were selected based on experts’ opinion, who built the original SRQ questionnaire and assisted us in selecting the most relevant questions for our research. The questionnaires were used in all 3 stages of the study (SRQ-7).p = 0.007) and low education . No significant differences were found in EPDS, GAD-7 and SRQ-7 scores, between those lost to follow-up and participants in the second interview (not shown). Between the first and second interview, 433 (44.9%) participants were lost to follow-up, and additional 118 (12.2%) participants were lost to follow-up between the second and third interview. Loss to follow-up was associated with low income  ,33 and GGAD-7 is a screening instrument which indicates the presence of symptoms of anxiety referred to in the DSM-IV . The queSome studies reported about challenges in screening of PPD and anxiety in specific populations since the different dialects within countries also raises the possibility of idiosyncratic elements, and individual ways of interpreting maternal depression. Several studies found psychological symptoms manifest differently from culture to culture ,50,51. TThe Self-Reporting Questionnaire (SRQ), developed by WHO experts, was designed for screening psychiatric illness, especially in developing countries, regardless of cultural context . This quIn this study, we used the GAD-7 EPDS and SRQ-7 questionnaires, for identifying anxiety, depression, and somatic disorders among mothers.Origin was defined by the women’s or their mothers’ country of birth (Israeli-Native-Born (INB), Ethiopian Jew (ETH), and Former-USSR Jew (FSU)). Information on a broad range of variables was collected at study intake, 6–8 weeks postpartum and at 12 months postpartum (concurrent variables). Socio-demographic, family history and pregnancy variables measured at study intake included maternal age , religiosity , marital status , maternal years of education (<13 vs. ≥13), income , smoking during pregnancy (yes vs. no), obstetric history including conception (spontaneous vs. fertility treatment), birth type , parity , gestational age , birth weight , gender, multigestation (yes vs. no), breastfeeding at 6–8 weeks (yes vs. no), and stressful life events in the previous year  .Descriptive characteristics of the study population were presented and compared by origin groups using one-way ANOVA and chi-square tests, as appropriate. Medians of EPDS and GAD-7 scores were presented, and distributions were compared by SRQ-7 as a dichotomous score (0 vs. ≥1), using Mann–Whitney test. The associations between origin and the study scales of mental disorders as continuous variables were assessed using generalized linear models where univariate models were followed by multivariable models, controlling for variables that were significantly associated with the outcomes in univariate models . p-values.Statistical analysis was performed with IBM SPSS Statistics for Windows, Version 25.0 . We present regression coefficients β and The study protocol was approved by the Institutional Review Board of the Israeli Ministry of Health, IRB #34, 2016, Hillel-Yaffe Medical Center, IRB #102, 2016, Shamir Medical Center, IRB #267, 2016, and Kaplan Medical Center, IRB #77, 2017. p < 0.001). The largest gap between the groups was observed in maternal education; only 33% of ETH had >12 years of education, whereas more than 62% of both other groups had more than 12 years of education. Similarly, ETH women were more likely to come from a household with lower than the average income . Among married women, low spousal support was reported by 9.5% of ETH women, compared with 4.5% among FSU women and 3.6% among INB women. ETH women had less prenatal care during pregnancy, with 12.7% having none or partial perinatal care, compared with 9.9% among INB and 5.0% among FSU, and higher prevalence of late (>40 week) deliveries . Additionally, ETH women had the highest rates of cesarean and instrumental births (35.4%) compared to INB (29.4%) and FSU women (29.9%).Taken together across the study population, as shown in Prevalence rates of positive scores of all three mental disorders by origin in the three time points of the study are presented in The overlap of prevalent cases in positive EPDS, GAD-7 and SRQ-7 at each interview is presented in p = 0.001; β = −0.678, p = 0.020; and β = −1.072, p = 0.007; right after birth, 6–8 weeks, and 12 months postpartum, respectively). FSU origin was negatively associated with EPDS after birth , and negatively associated with GAD-7, 12 months postpartum . In contrast, Ethiopian and FSU origin were positively associated with SRQ-7 scores after birth . Other factors that were associated with SRQ-7 included maternal age of 18–24 years, compared with 35+ years for high score of SRQ-7 after birth . Low education (<12 years) was associated with SRQ-7 scores in all three stages of the study . Stressful life events were consistently strongly associated with all mental states at all three stages of the study . The associations with SRQ-7 tended to be somewhat weaker . When a variable of sense of racism was entered into the models, it was found to be a significant risk factor for SRQ-7, but its presence weakened the association between origin and SRQ-7 (not shown).Studying the associations between origin and EPDS, GAD-7, and SRQ-7 scores , EthiopiThe present study aimed to investigate the association between migration and mental disorders postpartum. The main finding of this study is that compared to nonimmigrant mothers, mothers of both immigrant groups were more likely to report on somatic symptoms. In this study, we present the prevalence of somatization that was found to vary across the immigrant groups, depending on maternal age, educational level, and life events, in the different three time points of interview. In our first hypothesis, PPD, anxiety and somatic symptoms would be significantly associated with origin and migration because of the stress that has been associated with migration or due to being from an immigrant family and its consequences ,15,17. MIn our study, the overall prevalence of positive EPDS score ≥ 10) 6–8 weeks postpartum was 4.7%, which is identical to the prevalence found in a study of Mother and Child Health Clinics in Israel from 2014–2015 , and sim0 6–8 weeOur findings of the associations between psychosomatic symptoms, EPDS and GAD-7 scores are consistent with worldwide literature and suggest that among immigrants in Western countries, somatization is a manifestation of other mental disorders ,26,30. EDepression is an emotional disorder whose expression differs between the Western and non-Western world . ReportsDepression, anxiety and somatoform disorders are the most prevalent disorders in primary care settings . Indeed,Our findings suggest that somatic symptoms are probably a core component of the depressive syndrome; our results show a strong association of somatization with depression and with anxiety, and that they add another dimension not fully appreciated by the other scales. These results are consistent with other studies, which found that in over 50% of cases, comorbidities existed between depression, anxiety and somatization ,68. StudWe examined the course of variation in the rate of mental disorders throughout the postpartum year. To avoid selection bias, we examined rates of depression among women who participated in the second phase of the study compared with women lost to follow-up and we found similar depression rates . In our study, the rate of mental disorders was the highest after birth, with a subsequent decline in the rate of disorders in the different origin groups. Few studies considered the variation of PPD rates, yet there is no consensus about the course of PPD during the first year postpartum. Although some studies reported remission of PPD in the first year postpartum ,76, otheThe present study found that the most persistent variable associated with all postnatal mental disorders was stressful life events in the past year. Our results are consistent with numerous epidemiological studies ,80,81 whOur study’s limitations include the lack of information on maternal mental state while pregnant which can influence postpartum mental health ,83 and lOur study has several strengths. First, the present study is among the first to examine the validity of psychosomatic symptoms across cultural groups. Furthermore, our findings support a vast literature illuminating cultural-based differences in expression of mental psychopathology ,92. CrosIn conclusion, although psychological distress has been observed to be higher among immigrants than among native populations, little is known about the prevalence, number, and severity of somatic symptoms associated with psychological distress in the immigrant population. The findings presented here, based on a unique database representing Jewish Israeli-, FSU- and Ethiopia-born women in Israel, extend our knowledge in the field. The findings of the study raise the question of whether screening tests used to detect depression at MCHC and in the HMO clinics are adapted to Israeli mothers in general and immigrant mothers, or whether a cultural adjustment is needed to improve and more accurately identify mental disorders among Israeli populations. Somatization is a challenge for health professionals due to its vague nature. In this regard, clinical management of immigrant patients should include further efforts to address emotional distress, with special attention to cultural differences. In addition, more research is needed to explore this potential relationship between psychosomatic symptoms and depression/anxiety further.


Cytomegalovirus (CMV) is the most common cause of congenital infection, with a wide spectrum of clinical manifestations and different grade of severity. We report the case of a male baby born at term with an early prenatal diagnosis of severe intracranial hemorrhage (ICH), with no other evident risk factors. Urine and blood sample were tested for CMV-DNA, and diagnosis of congenital CMV infection was established. This case describes intracranial hemorrhage as uncommon although possible sign of early fetal CMV infection. Considering that pathogenic factors cannot be defined in 25 % of term neonates with ICH, this case report highlights the importance of CMV screening in pregnant women and in term infants with prenatal ICH of unknown origin. CMV is the most common cause of congenital infection with a wide spectrum of manifestations. Approximately 10 % of neonates with congenital CMV (cCMV) infection are symptomatic at birth with clinical manifestations including jaundice, petechiae, purpura, hepatosplenomegaly, microcephaly and neurological symptoms, including intracerebral calcifications , sensorineural hearing loss, cerebellar and hippocampal hypoplasia, cortical dysplasia  and retinitis. Neurodevelopmental impairment in childhood is common . IntraveMR was born at 38 weeks of gestational age (GA) from elective cesarean section. At birth: weight 2350 g (5−10° pt), length 45 cm (5° pt), head circumference 31 cm (<5° pc). Doppler flow at obstetric ultrasounds was regular. Placenta normal in shape and perfusion. The Apgar score was 8 at 1st min., 9 at 5th min.At beginning of pregnancy, the mother was diagnosed as immune to rubella and she was negative for toxoplasmosis specific antibodies (IgG and IgM) throughout all the pregnancy. Only one determination of serological status for CMV at 11th week of GA was available(IgG positive and IgM negative). A maternal febrile episode in peri-conceptive period was reported. No maternal trauma reported in early pregnancy. Parents were not consanguineous and there was no family history of any bleeding disorders or stroke. No maternal use of cocaine or warfarin or anticonvulsant was reported.A prenatal diagnosis of ICH was suspected during an ultrasound performed at 20th week of GA and it was confirmed at 25th week of GA through a fetal brain Magnetic Resonance Imaging (MRI) scan .The prenBecause of these prenatal findings, immediately after birth the neonate was admitted in our Neonatal Intensive Care Unit for further evaluations.At birth physical examination revealed micro-purpuric elements on face and upper thorax, microcephaly, mild upper limbs muscular hypertonicity, abnormal deep tendon reflexes , jaundice.Laboratory evaluations were performed, including complete blood cell count, coagulative profile and liver and kidney function tests. Examinations for suspected congenital coagulopathy causing cerebral bleeding were performed : all these exams resulted normal. Moreover, gene sequencing for MTHFR/Leiden Factor polymorphism resulted wild type. Screening for metabolic diseases at birth was negative.Cranial ultrasound performed on first day of life showed left cerebral hemisphere prevailing on the right, a poroencephaly (2.3 cm of diameter) on the right side with “ex vacuo” ventricle enlargement  till Silvian fissure. A germinolytic cyst on the left side and hyperechoic spots in the left peritrigonal parenchyma were found. Corpus callosum was poorly visible in its anterior portion. Third and fourth ventricles were normal-sized .Fig. 2CeA postnatal MRI scan confirmed the previous finding. It showed poroencephaly in the right fronto-temporal and insular zone with “ex vacuo” ventricle enlargement, reduced volume of the right cerebral hemisphere, with striatum nucleus and thalamus partially involvement with wallerian degeneration of the corticospinal bundle. MR angiography did not show arterial and venous malformations nor thrombosis. An abnormal development of the middle-lower right frontal cortex was highlighted, which showed a polylobate appearance due to reduced furrows width and increased number of turns confirming the micropolygyria extended up to the right parietal lobe .Fig. 3CeThe electroencephalogram showed cortical abnormal activity in frontal-temporal-parietal cortex.Abdomen and cardiac ultrasound examinations, audiological (TEOAE) and ophthalmological evaluation were performed and all were normal.3 and 449 copies/ mm3 in blood. Therefore, the patient received diagnosis of congenital CMV infection and it was classified as a severe symptomatic one because of central nervous system involvement . According to current guidelines on the 15th day of life he started antiviral treatment with oral valganciclovir  for 6 months.Considering the micropolygyria at MRI scan, on the fifth day of life we searched for CMV DNA in body fluid and we detected in urine 10.273.900 copies/mmDischarged at the 17th day of life, the patient was admitted in our outpatient program for perinatal infectious diseases. No side effects were reported as consequence of the antiviral therapy. Evoked auditory brainstem response and ophthalmological evaluations were performed and resulted normal. Neurological examination at three months of age underlined persistence of neurological impairment more evident at the left side and he was admitted to physio-kinesiotherapy and neuro developmental follow up. At 18 month of life he presented global delay in development with pyramidal signs in the left hemisome. In particular he achieved head and trunk control and from the supine position he reached the prone and vice versa; with double support he maintained the standing position and took a few steps. His language were characterized by lallation and some simple bisyllabic phonemes. The EEG trace showed anomalies with potential epileptiform significance on the right hemisphere without critical episodes so that he did not start antiepileptic therapy.Intracranial hemorrhage is a rare complication of cCMV infection. Two different hypotheses have been advanced to explain this condition.One hypothesis considers CMV as cause of direct neuronal damage, due to its neurotropic nature, especially in early gestational age, resulting in cortical dysplasia and hippocampus and cerebellum hypoplasia.A second hypothesis considers CMV as cause of vasculitis that can affect blood vessels of the central nervous system, triggering thrombotic or hemorrhagic processes, even in absence of apparent coagulopathy ,9. This Suksumek et al.  reportedOur case, apparently very similar to this one, differs however for the earlier gestational age at CMV infection. In fact, the intracranial hemorrhage in utero was suspected at 20th week of GA and the earlier infection is in line with the finding of micropolygyria, microcephaly with global growth retardation and the severe neurological impairment showed since birth. The two cases may share the common origin but the early onset in our case lead to a different and more severe clinical picture. Moreover, in our case there was a very complex cerebral picture not only consequence of an intraventricular hemorrhage. In fact, cerebral fetal damage did not probably originate from the germinal matrix, related for example to the immaturity of its vessels, because it would have been restricted to the germinal matrix or at least extent into the lateral ventricles. We speculated that our patient suffered from a complex ischemic-hemorrhagic phenomenon in utero caused by CMV infection, which covered a wide area of parenchyma, including also but not only germinal matrix, where neural precursors originate. In prenatal MRI, an abnormal signal pattern in sub plate was reported and it may correlate with an anomalous cortical organization, which results in the micropolygyria in the same areas detected in the post-natal MRI.Maternal history may suggest a very early infection in the first trimester or a reinfection  in the eParents of neonate received a full prenatal counseling on ICH diagnosis otherwise, they decided to continue pregnancy and asked for the full medical care for the neonate.In conclusion, in our patient, diagnosis of fetal ICH forerun the diagnosis of congenital CMV. ICH affects 0.5/1000 of symptomatic term infants and in 25 % of these cases, pathogenic factors cannot be defined. This case report highlights the importance of testing pregnant women and neonate for CMV infection in case of unexplained fetal intracranial bleeding as a possible etiology.Conceptualization: LC, FR.Supervision. LC, FR.Writing and editing: LC, CCoppola, MV, SS.Data Collection: VE, CColinet, CP.Review: LC, MV, SS.Not applicable.The parents of the neonate gave as consent for publication of the clinical history and images.No funding to declare.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.